Multiple myeloma (MM) is a neoplastic disease deriving from an abnormal proliferation of monoclonal plasma cells in the bone marrow. The survival of MM patients varies from less than 6 months to more than 10 years depending on the stage of disease at diagnosis and prognostic factors. Before 2021, in Italy three current standard treatments were approved for elderly or younger patients with significant comorbidities not eligible for autologous stem cell transplantation (ASCT): bortezomib-melphalan-prednisone (VMP), melphalan-prednisone-thalidomide (MPT) and lenalidomide with low-dose dexamethasone (Rd). Daratumumab is a human IgGk monoclonal antibody that targets CD38, that showed clinical benefit in combination with standard-of-care therapy. The addition of Daratumumab (Dara) to VMP and Rd has created two new standards-of-care regimens Dara-VMP and Dara-Rd, which were approved by the EMA in October 2019, and by the AIFA at the beginning of 2021, based on the results of two large phase 3 studies. A consistent fraction of elderly patients with cancer and co-morbidities are at increased risk of developing frailty (an emergent geriatric syndrome), as well as physical and cognitive decline, with negative effect on dependance, nutrition and lifestyle, and eventually on responsiveness to and efficacy of treatments. A frailty scale was recently described that categorized patients with MM as fit, intermediate or frail based on age, comorbidities, and physical and cognitive functioning. The frailty score was a predictor of death, progression of the disease, toxicity and drug discontinuation. The aim of this study was to compare the first line standard treatments, the triplet VMP versus the doublet Rd, that were available when the study was designed. Until 17th December 2021, 228 patients were enrolled in this trial and randomized to VMP vs Rd. Since Dara-VMP and Dara-Rd have recently become the new standard regimens, in this amendment of the study, daratumumab is added to VMP and Rd. In this project, we will compare available first line standard treatments, the triplet VMP versus the doublet Rd with or without daratumumab (Dara-VMP, Dara-Rd), in an unselected population of patients ≥ 65 years affected by MM in every day clinical practice. In the last decade, many novel and expensive drugs have been approved for this disease, yet the general older population is not adequately represented in validating trials. Nevertheless, the results and treatments derived from those registrational trials have often been applied to the real-life older population, with a high risk to produce a negative impact on patient functional capacity and ability to carry out daily tasks, cognitive function, mental status, nutritional condition, social situation/capability to stay at home and finally affecting their quality of life (QoL) and OS. The main aim of the project is to evaluate the best initial treatment for elderly MM patients and to compare benefits, risks, QoL and costs of currently available, standard treatments according to the patient frailty profile.
All patients will be randomized in a 1:1 ratio to receive: ARM A (enrollment closed): Bortezomib (V): * 1.3 mg/m2 subcutaneously on days 1, 4, 8, 11, 22, 25, 29 and 32 in cycles 1-4; * 1.3 mg/m2 subcutaneously on days 1, 8, 22 and 29 in cycles 5-9. Melphalan (M): \- 9 mg/m2 orally on days 1, 2, 3 and 4 of each cycle. Prednisone (P): \- 60 mg/m2 orally on days 1, 2, 3 and 4 of each cycle. Each cycle is to be repeated every 42 days. Duration: Maximum 9 therapy cycles can be performed. After 9 cycles, patients will be observed until progression disease or the start of a new line of therapy. ARM A2: Bortezomib (V) 1. 3 mg/m2 subcutaneously twice weekly on weeks 1, 2, 4, and 5 of cycle 1 (days 1,4,8,11,22,25,29,32) and once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9 (days 1,8,22,29) Melphalan (M):- 9 mg/m2 orally on days 1, 2, 3 and 4 of each cycle. Prednisone (P): \- 60 mg/m2 orally on days 1, 2, 3 and 4 of each cycle. Daratumumab (Dara) 16 mg per kilogram of body weight or 1800 mg Daratumumab subcutaneous (SC) (according to local clinical practice) with oral or intravenous dexamethasone (to manage infusion reactions) at a dose of 20 mg once weekly in cycle 1 (days 1,8,15,22,29,36), every 3 weeks in cycles 2 through 9 (days 1,22), and every 4 weeks thereafter until disease progression or unacceptable toxic effects. Dexamethasone at a dose of 20 mg was substituted for prednisone on day 1 of each cycle. ARM B (enrollment closed): Lenalidomide (R): \- 25 mg orally on days 1-21 of each cycle. Dexamethasone (d): \- 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycles. Duration: patients will receive treatment until any sign of progression or intolerance. ARM B2 Lenalidomide (R): \- 25 mg orally on days 1-21 of each cycle. Dexamethasone (d): \- 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycles. Daratumumab (Dara) intravenous at a dose of 16 mg per kilogram of body weight or 1800 mg Daratumumab subcutaneous (SC) (according to local clinical practice) once weekly during cycles 1 and 2, every 2 weeks during cycles 3 through 6, and every 4 weeks thereafter; preinfusion medications were administered approximately 1 hour before each daratumumab dose.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
450
Subcutaneous use
Oral use
Oral use
Oral use
Oral use
Subcutaneous Injection
Dipartimento di Biotecnologie Molecolari e Scienze per la Salute
Torino, TO, Italy
Progression-free survival (PFS)
Number of months from the date of randomization to the date of first observation of PD, or death from any cause as an event.
Time frame: 5 years
Overall response rate (ORR)
Overall response rate will include complete response (CR), very good partial response (VGPR) and partial response (PR) using the International Response Criteria. Responders are defined as subjects with at least a PR.
Time frame: 5 years
Duration of response (DOR)
Time between first documentation of response and PD. Responders without disease progression will be censored either at the time of lost to FU, at the time of death due to other cause than PD, or at the end of the study.
Time frame: 5 years
Overall survival (OS)
Time between randomization and death. Subjects who die will be censored at time of death as an event, regardless cause of death.
Time frame: 5 years
Progression-free survival 2 (PFS2)
Time from randomization to objective tumor progression on next-line treatment or death from any cause.
Time frame: 5 years
Time to next therapy (TNT)
Time to next therapy will be measured from the date of randomization to the date of next anti-myeloma therapy. Death due to any cause before starting therapy will be considered an event.
Time frame: 5 years
Time to progression (TTP)
Time to progression will be measured from the date of randomization to the date of first observation of PD, or deaths related to PD.
Time frame: 5 years
Adverse events
Safety will be evaluated by assessing the incidence, severity and type of AEs according to NCI-CTCAE v. 4.0.
Time frame: 5 years
Rate of treatment discontinuation or death for toxicity
Incidence of treatment discontinuation for toxicities as well as the rate of death for toxicity will be evaluated during the entire duration of the trial (toxicities evaluated according to NCI-CTCAE v. 4.0)
Time frame: 5 years
Frailty score
Validation of Myeloma Frailty Score (fit score=0; intermediate-fitness score=1, and frail score≥2) that assess comorbidities, cognitive and physical status in real population according to geriatric assessment and considering patients' non-Myeloma polydrug therapies.
Time frame: 5 years
Quality of Life through Health-Related QoL (HRQoL)
Quality of Life will be evaluated through questionnaire: EORTC-QLQ-C30 (a generic, multidimensional, cancer-specific QoL questionnaire).
Time frame: 5 years
Quality of Life through Health-Related QoL (HRQoL)
Quality of Life will be evaluated through questionnaire for MM patients: QLQ-MY20 (a specific 20- item MM module).
Time frame: 5 years
Quality of Life through Health-Related QoL (HRQoL)
Quality of Life will be evaluated through questionnaire: EQ-5D-5L (a generic assessment of five health categories and overall health score).
Time frame: 5 years
Direct health related costs and indirect costs
Health-related costs will be reported through Questionnaires For Patients Costs Evaluation reported in the protocol evaluating working activities.
Time frame: 5 years
Direct health related costs and indirect costs
Health-related costs will be reported through Questionnaires For Patients Costs Evaluation reported in the protocol evaluating care assistance.
Time frame: 5 years
Direct health related costs and indirect costs
Health-related costs will be reported through Questionnaires For Patients Costs Evaluation reported in the protocol evaluating health care visit.
Time frame: 5 years
Risk of infectious complications
Infectious risk complications will be evaluated through a scale evaluating the number of adverse events, severity, type of infection, need for hospitalization (yes/no), number of days of suspension of study treatment. All these data will be combined in the statistical analysis to combine different outcome of treatments.
Time frame: 5 years
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